Fibrin and synthetic sealants offer a significant advantage over pure hemostats because they do not rely on the full complement of blood factors to produce hemostasis. Sealants provide all the components necessary to prevent bleeding and will often prevent bleeding from tissues where blood flow is under pressure and the damage is extensive.

Source: CryoLife

These products have the potential to replace sutures in some cases where speed and strength of securement are priorities for the surgical procedure.

Biologically active sealants typically contain various formulations of fibrin and/or thrombin, either of human or animal origin, which mimic or facilitate the final stages of the coagulation cascade. The most common consist of a liquid fibrin sealant product in which fibrinogen and thrombin are stored separately as a frozen liquid or lyophilized powder. Before use, both components need to be reconstituted or thawed and loaded into a two-compartment applicator device that allows mixing of the two components just prior to delivery to the wound. Because of the laborious preparation process, these products are not easy to use. However, manufacturers have been developing some new formulations designed to make the process more user friendly. Leaders in biologic surgical sealant space include Baxter International and Johnson & Johnson’s Ethicon Biosurgery division, but there are a number of smaller suppliers as well, in what has become an increasingly crowded field.

Compared to biologically active sealants containing fibrin and other human- or animal-derived products, synthetic sealants represent a much larger segment of the sealant market in terms of the number of competitors, variety of products, and next-generation products in development. Non-active synthetic sealants do not contain ingredients such as fibrin that actively mediate the blood clotting cascade, rather they act as mechanical hemostats, binding with or adhering to the tissues to help stop or prevent active bleeding during surgery.

Synthetic sealants represent an active category for R&D investment in large part because they offer several advantages over fibrin-based and other biologically active sealants. First and foremost, they are not derived from animal or human donor sources and thus eliminate the risks of disease transmission. Moreover, they are typically easier to use than biological products, often requiring no mixing or special storage, and many of these products have demonstrated improved sealing strength versus their biological counterparts. Synthetic products also have the potential to be more cost-effective than their biologically active counterparts. Leaders in the synthetic surgical sealants space include Baxter International Inc., CryoLife, CR Bard, and Ethicon/J&J; however, there are many up-and-coming competitors operating in this segment of the market with some interesting next-generation technologies that could gain significant traction in the years ahead. Moreover, unlike the fibrin sealants segment, where most products have more general indications for surgical hemostasis, a good number of competitors in the synthetic sealant field are focused on specific clinical applications for their products, such as cardiovascular surgery, plastic surgery, or ophthalmic surgery.

Source: Report #S192 (pub. 2014)

The non-active hemostats segment of the market includes a variety of scaffolds, patches, sponges, putties, powders, and matrices made of various nonactive materials that act mechanically to stop/absorb active bleeding, often in conjunction with manual compression, during surgical procedures as well as emergency use. Many of the companies active in the first two market segments discussed above also participate in this sector, including Ethicon/J&J, CR Bard, Baxter, and CryoLife, but there are also many other companies that compete in the hemostats market worldwide.

Published July 2016, Report #S290, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022”. Available online.

See Report #S192, “Worldwide Surgical Sealants, Glues, and Wound Closure Markets, 2013-2018”. (Note: This report has been superceded by the August 2016 Report #S290.)

Sutures have been in use for potentially thousands of years, and staples for the last several decades. Both have been frequently been the target of new development in wound closure and management, with competition in the form of advanced wound closure, whether surgical sealants, glues, hemostats, and even other mechanical wound closure. Novel wound closure technologies have decidedly gained enough credibility in clinical practice to displace volume in sutures and staples.

Sutures and Staples Are Not Fading…

Manufacturers of sutures and staples have not sat idly and watched their share erode. Indeed, the development of bioresorbable sutures and other novel suture types, the development of sophisticated stapling and suturing endoscopic instrumentation and other developments have begun to erode the share loss. Consequently, the shift “away” from sutures and staples has ebbed, such that the aggregate swing in market shares is no more than 3% compared to the swing projected three years ago of nearly 7% (see link).

The vast majority of sutures, staples, and endostaples are used to close procedures involving acute surgical wounds. Typically, chronic wounds do not involve the use of sutures and staple products unless some degree of surgical intervention is employed to remove necrotic tissue or to create a new acute wound bed to aid healing.

Sutures are classified as absorbable or non-absorbable; monofilament, multifilament or braided; and natural or synthetic. Absorbable or non-absorbable describes the suture’s effective life within tissue. Absorbable sutures lose the majority of their tensile strength within 60 days after use. Non-absorbable sutures are resistant to living tissue and do not break down. Monofilament, multifilament, and braided describe the structure or configuration of the suture based on the number of strands used to manufacture the product. Natural or synthetic refers to the origin of the suture. Natural suture materials include surgical gut, chromic gut, catgut and silk. Catgut is made from the natural collagen fibers found in the intestine of sheep, goats, cattle, hogs and horses. (It was never made from the gut of cats.) It is debatable whether catgut should continue to be used for suturing wounds, since cotton is cheaper and cotton or synthetic threads are less likely to cause infection. Synthetic suture materials include nylon, polyester, stainless steel, polypropylene, polyglycolic acid (PGA), polyglycolide-co-caprolactone (PGCL), and polydioxanone.

Suture products consist of two component parts, the needle and the suture. These can be found in a wide range of sizes and types, made of a range of materials, and the method of attachment of the suture to the needle can involve a variety of methods. Sutures are divided into braided and monofilament categories. Braided sutures are typically more pliable than monofilament and exhibit better knot security. Monofilament sutures are wirier and may require a more secure knot; however, they cause less tissue drag than braided sutures, a characteristic that is especially important in cardiovascular, ophthalmic and neurological surgery

Stapler devices are an evolution of suture technology. The goal of stapler products is to avoid infection and make the wound closure procedure easier and faster. Staples are made of stainless steel and biomaterials and are used to join internal tissues, reconstruct or seal off organs, remove diseased tissue, occlude blood vessels, and close skin incisions and lacerations. They are primarily used during surgery as internal and/or external closure devices.

Staples are available in an assortment of sizes and features and stapler devices have been developed for specific procedures as well as for multiple uses.

Internal staplers are used to approximate (or close) internal tissues and organs. The devices may be reusable or disposable. Some disposable staplers may be reloaded several times during the course of a single patient surgical procedure, before being discarded.

The most recent internal staplers are used to perform minimally invasive surgical procedures. These allow the surgeon to endoscopically secure internal wounds instead of having to operate through an open procedure. Moreover, internal biodegradable staples obviate the need for staple removal. Such staples are ideally suited to laparoscopic surgery and are delivered via procedure-specific laparoscopic instruments. However, most staples are still made of stainless steel and when used for internal stapling procedures, whether open or laparoscopic, are not removed after healing. Skin staples are removed after the incision is healed.

Probably the major benefit of staples is that they can be applied more rapidly than sutures and can be placed precisely without requiring the skill necessary for suturing. This also means increased safety for the patient, and patients can often be discharged more rapidly if procedures are stapled rather than sutured.

While cosmetically acceptable results are usually obtained, staplers normally are not used in highly visible areas such as the face. Here, surgeons will still close by hand to minimize any scarring. In many skin closure procedures, sutures have begun to be replaced by cyanoacrylate glues. However, the ideal alternative to suturing has not yet been developed; for example, cyanoacrylate glues used for external skin closure are only one-fifth as strong as sutures.

Sealants and glues are emerging as important adjunctive tools for sealing staple and suture lines, and some of these products also are being employed as general hemostatic agents to control bleeding in the surgical field. Manufacturers have also developed surgical sealants and glues that are designed for specific procedures – particularly those in which staples and sutures are difficult to employ or where additional reinforcement of the internal suture/staple line provides an important safety advantage.

Surgical sealants are made of synthetic or naturally occurring materials and are commonly used with staples or sutures to help completely seal internal and external incisions after surgery. In this capacity, they are particularly important for lung, spinal, and gastrointestinal operations, where leaks of air, cerebrospinal fluid, or blood through the anastomosis can cause numerous complications. Limiting these leaks results in reduced mortality rates, less post-operative pain, shorter hospital stays for patients, and decreased health care costs.

Although some form of suturing wounds has been used for thousands of years, sutures and staples can be troublesome. There are procedures in which sutures are too large or clumsy to place effectively, and locations in which it is difficult for the surgeon to suture. Moreover, sutures can lead to complications, such as intimal hyperplasia, in which cells respond to the trauma of the needle and thread by proliferating on the inside wall of the blood vessel, causing it to narrow at that point. This increases the risk of a blood clot forming and obstructing blood flow. In addition, sutures and staples may trigger an immune response, leading to inflamed tissue that also increases the risk of a blockage. Finally, as mentioned above, sutured and stapled internal incisions may leak, leading to dangerous post-surgical complications.

These are some of the reasons why surgical adhesives are becoming increasingly popular, both for use in conjunction with suture and staples and on a stand-alone basis. As a logical derivative, surgeons want a sealant product that is strong, easy-to-use and affordable, while being biocompatible and resorbable. In reality, it is difficult for manufacturers to meet all of these requirements, particularly with biologically active sealants, which tend to be pricey. Thus, for physicians, there is usually a trade-off to consider when deciding whether or not to employ these products.

Surgical sealants, glues, and hemostats can be divided into several different categories based on their primary components and/or their intended use.

The following is excerpted from sections of Report #S192, “Worldwide Surgical Sealants, Glues, and Wound Closure Markets, 2013-2018”, published by MedMarket Diligence, LLC.

Sealants and glues in wound closure may be comprised of naturally-occurring (bioactive) ingredients (including from human or animal) or may be synthetic in origin. Many bioactives are comprised primarily of fibrin sealant, give its evolutionary design in stopping bleeding and sealing wounds. Bioactive sealants offer the benefit of well documented performance with lack of toxicity, but with the existing sealants on the market, the strength of the closure provided falls somewhat short of what is needed for sealants to be used autonomously in all but the least challenging closure conditions. For this reason, a wide range of other biologically active agents with higher sealant strength are in various phases of evaluation (See “Gecko feet, mussel shells and other sticky things” at link).

Bioactive sealants that on the market and in development are detailed at link.

Compared to biologically active sealants containing fibrin and other human- or animal-derived products, synthetic sealants represent a much larger segment of the sealant market in terms of the number of competitors, variety of products, and next-generation products in development. Non-active synthetic sealants do not contain ingredients such as fibrin that actively mediate the blood clotting cascade, rather they act as mechanical hemostats, binding with or adhering to the tissues to help stop or prevent active bleeding during surgery.

Synthetic sealants that are on the market and in development are detailed at link.

For example, the two graphics below illustrate the wound closure markets in Germany and the United Kingdom. To have fully compared the markets in these two countries aside from differences in population, we might have presented per capita values in the sales, but even without doing so it is clear that relative sizes and growth rates in the two countries are sufficiently different to warrant attention in local efforts to market these products.

Source: “Worldwide Surgical Sealants, Glues, and Wound Closure Markets, 2013-2018”, Report #S192; published by MedMarket Diligence, LLC. (Note: This report has been superceded by the August 2016 Report #S290.)

Of late, I have needed to re-emphasize the difference between absolute and relative growth in medtech markets (and its importance). So, here it is again, this time regarding surgical sealants and other wound closure products.

The lowest relative rate of growth in this industry is the well-established sutures and staples segment. Sales of these products globally, even supported by innovations in bioresorbables and laparoscopic delivery technologies, are only growing at a 5.6% compound annual growth rate from 2013 to 2018. By comparison, growth of sales of surgical glues and sealants is at 9.4% for 2013-2018.

But from an absolute sales growth point of view, sales of sutures and staples will go from $5.2 billion to $6.9 billion, or absolute growth of $1.7 billion. Simultaneously, the relatively high growth in surgical glues and sealants translates to the absolute growth from 2013 to 2018 of only $0.9 billion.

Biologically active sealants typically contain various formulations of fibrin and/or thrombin, either of human or animal origin, which mimic or facilitate the final stages of the coagulation cascade. The most common consist of a liquid fibrin sealant product in which fibrinogen and thrombin are stored separately as a frozen liquid or lyophilized powder. Before use, both components need to be reconstituted or thawed and loaded into a two-compartment applicator device that allows mixing of the two components just prior to delivery to the wound. Because of the laborious preparation process, these products are not easy to use. However, manufacturers have been developing some new formulations designed to make the process more user friendly.

Selected Biologically Active Sealants, Glues, and Hemostats

Company

Product Name

Description/ (Status*)

Asahi Kasei Medical

CryoSeal FS System

Fibrin sealant system comprising an automated device and sterile blood processing disposables that enable autologous fibrin sealant to be prepared from a patient's own blood plasma in about an hour.

Baxter

Artiss

Fibrin sealant spray

Baxter

Tisseel

Biodegradable fibrin sealant made of human fibrinogen and human thrombin. For oozing and diffuse bleeding.

Evicel is a new formulation of the previously available fibrin sealant Quixil (EU)/Crosseal (US). Does not contain the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic, nor does it contain synthetic or bovine aprotinin, which reduces potential for hypersensitivity reactions.

J&J/Ethicon

Evarrest

Absorbable fibrin sealant patch comprised of flexible matrix of oxidized, regenerated cellulose backing under a layer of polyglactin 910 non-woven fibers and coated on one side with human fibrinogen and thrombin.

Company is working with Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) to develop a sheet-type surgical fibrin sealant. Product combines KAKETSUKEN's recombinant thrombin and fibrinogen technology with Teijin's high-performance fiber technology to create the world's first recombinant fibrin sealant on a bioabsorbable, flexible, nonwoven electrospun fiber sheet.

The Medicines Company (TMC)

Raplixa (formerly Fibrocaps)

Sprayable dry-powder formulation of fibrinogen and thrombin to aid in hemostasis during surgery to control mild or moderate bleeding.

The Medicines Company (TMC)

In development: Fibropad patch

FDA accepted company's BLA application for Fibrocaps in April 2014 and set an action date (PDUFA) in 2015. In November 2013, the European Medicines Agency agreed to review the firm's EU marketing authorization application. Status update in report #S192.

Vascular Solutions

D-Stat Flowable

Thick, but flowable, thrombin-based mixture to prevent bleeding in the subcutaneous pectoral pockets created during pacemaker and ICD implantations.

Sealants, glues, hemostats, and other products in wound closure and securement offer benefits that vary by clinical area, but the nature of that benefit also varies by the type of end-point (benefit) the product achieves — does it provide a life-saving benefit? A time-saving? Cost-savings? A cosmetic or aesthetic benefit?

Accordingly, by examining the volume of procedures for which closure and securement products provide which kind of benefit is crucial to understanding demand, especially between competitive products.

Below is a categorization of benefits ranging from the critical (I) to the aesthetic (IV).

Criteria for Adjunctive Use of Hemostats, Sealants, Glues and Adhesion Prevention Products in Surgery

Wounds may be classified according to their depth and whether underlying tissues are damaged. Partial-thickness wounds do not intrude through the dermis and can heal by regeneration; full-thickness wounds involve both the epidermis and dermis, and sometimes underlying tissues as well. They generally heal by scar formation. Wound classification by morphology is shown below:

Type

Tissue Characteristics

Etiology

Prognosis for Healing

Partial thickness

Involves entire epidermis and portions of dermis.

Friction, pressure, small cuts, minor burns.

Heal within 10-18 days, epidermal element germinates and migrates up to the epithelial layer. Heals without significant scarring or functional impairment.

Deep partial thickness

Involves entire epidermis and almost entire dermis.

Friction, cuts, significant burns.

Healing within 20-35 days.

Full thickness

Involves epidermis and dermis; may extend into subcutaneous tissue. Sweat glands and hair follicles are destroyed.

The global market for surgical sealants, glues, hemostats, vascular closure devices, sutures/staples, and tapes is the subject of Report #S192.

See also the October 2015 report, “Worldwide Wound Management, Forecast to 2024:Established and Emerging Products, Technologies and Marketsin the Americas, Europe, Asia/Pacific and Rest of World”, Report #S251.